Catalysis lies at the heart of countless chemical protocols, from the academic research laboratories to the chemical industry. A variety of products, such as medicines, fine chemicals, polymers, fibers, fuels, paints, lubricants, and a myriad of other value-added products essential to humans, would not be feasible in the absence of catalysts. These active compounds arbitrate the mechanism by which chemical transformations take place, thus enabling the commercially viable creation of desired materials. A homogeneous catalyst, where the catalyst is in the same phase as the reactants, is often desirable. One attractive property is that all catalytic sites are accessible because the catalyst is generally a soluble metal complex. Furthermore, it is possible to tune the chemo-, regio- and enantioselectivity of the catalyst. Homogeneous catalysts have a number of other advantages such as high selectivities, better yield, and easy optimization of catalytic systems by modification of ligand and metals. They are widely used in a number of commercial applications, but the difficulty of catalyst separation from the final product creates growing economic and environmental barriers to broaden their scope.
Despite the advantages of homogeneous catalytic systems and their wide use in a number of applications, many homogeneous catalytic systems have not been commercialized because of the difficulty encountered in separating the catalyst from final reaction product and the solvent. Removal of trace amounts of catalyst from the end product is essential since metal contamination is highly regulated especially by the pharmaceutical industry. Even with the extensive and careful use of various techniques such as distillation, chromatography, or extraction, removal of trace amounts of catalyst remains a challenge.
Heterogeneous catalyst systems appear to be the best logical solution to overcome the separation problems in homogeneous catalysis. The majority of the novel heterogenised catalysts are based on silica supports, primarily because silica displays some advantageous properties, such as excellent stability (chemical and thermal), good accessibility, porosity, and the fact that organic groups can be robustly anchored to the surface to provide catalytic centers. The common structural feature of these materials is the entrapment or anchoring of the dopant (catalytic) molecule in the pores of silica, a phenomenon which imparts unique chemical and physical properties to resulting hybrid silica. Anchoring can be achieved by covalent binding of the molecules or by simple adsorption; however covalent anchoring is robust enough to withstand the harsh reaction conditions and the catalyst can be reused several times. A vast majority of the industrial heterogeneous catalysts are high-surface-area solids onto which an active component is dispersed or attached.
Although attempts have been made to make all active sites on solid supports accessible for reaction, allowing rates and selectivities comparable to those obtained with homogeneous catalysts, only sites on the surface are available for catalysis thus decreasing the overall reactivity of the catalyst system. Another problem is the leaching of active molecule/complex from solid supports because of breaking of bonds between metal and ligand during catalytic reactions, which again necessitates separation of trace metals from final product. Catalyst recovery is often performed by filtration that reduces efficiency, and extractive isolation of products requires large amounts of organic solvents.
Consequently, new catalyst systems that allow for the rapid, selective chemical transformations with excellent product yield coupled with the ease of catalyst separation and recovery are much sought for “greening” the chemical manufacturing processes.
Nanomaterials, including nanoparticles, have emerged as sustainable alternatives to conventional materials, as robust, high-surface-area heterogeneous catalyst and catalyst supports. The nano-size of the particles increases the exposed surface area of active component of catalyst thereby enhancing the contact between reactants and catalyst dramatically and mimicking the homogeneous catalysts. The scientific challenge is the synthesis of catalyst in nano-size to allow facile movement of materials in the reacting phase and control over morphology of nanostructures to tailor the physical and chemical properties. The development of solution-based controlled synthesis of nanomaterials has made this possible without difficulty. Synthesis of single-crystal micro-pine structured nano-ferrites and their application in catalysis, Polshettiwar et al., Chem. Commun. 2008, 6318; Self-assembly of metal oxides into 3D nano-structures: Synthesis and nano-catalysis, Polshettiwar et al, ACS Nano. 2009, 3, 728.
Magnetic nanomaterials are envisaged to have major impacts on catalysis and many other areas, such as medicine, drug delivery and remediation. These inexpensive materials are accessible via simple synthesis and they can be easily enhanced/tuned by postsynthetic surface modifications. Controlling Transport and Chemical Functionality of Magnetic Nanoparticles, Latham et al., Acc. Chem. Res. 2008, 41, 411-420. Functionalized nanoparticles have emerged as feasible substitute to conventional materials as a robust, active, high-surface-area catalyst support. Magnetically Recoverable Chiral Catalysts Immobilized on Magnetite Nanoparticles for Asymmetric Hydrogenation of Aromatic Ketones, Hu et al, J. Am. Chem. Soc. 2005, 127, 12486-87; Expanding the Utility of One-Pot Multistep Reaction Networks through Compartmentation and Recovery of the Catalyst, Phan et al., Angew. Chem. Int. Ed. 2006, 45, 2209-12; Metal Supported on Dendronized Magnetic Nanoparticles: Highly Selective Hydroformylation Catalysts, Abu-Reziq et al., J. Am. Chem. Soc. 2006, 128, 5279-5282; Tuning Catalytic Activity between Homogeneous and Heterogeneous Catalysis Improved Activity and Selectivity of Free Nano-Fe2O3 in Selective Oxidations, Shi et al., Angew Chem. Int. Ed. 2007, 46, 8866-68; A Magnetic-Nanoparticle-Supported 4-N,N-Dialkylaminopyridine Catalyst: Excellent Reactivity Combined with Facile Catalyst Recovery and Recyclability, Dalaigh et al., Angew. Chem. Int. Ed. 2007, 46, 4329-32; The First Magnetic Nanoparticle-Supported Chiral DMAP Analogue: Highly Enantioselective Acylation and Excellent Recyclability, Gleeson et al. Chem. Eur. J. 2009, doi-10.1002/chem. 200900532. In view of their nano-size, the contact between reactants and catalyst increases dramatically, thus mimicking the homogeneous catalysts. They offer an added advantage of being magnetically separable, thereby eliminating the requirement of catalyst filtration after completion of the reaction. Nanoparticle-supported and magnetically recoverable palladium (Pd) catalyst: a selective and sustainable oxidation protocol with high turnover number, Polshettiwar et. al. Org. Biomol. Chem., 2009, 7, 37-40; Nanoparticle-supported and magnetically recoverable nickel catalyst: a robust and economic hydrogenation and transfer hydrogenation protocol, Polshettiwar et. al. Green Chem., 2009, 11, 127-131; Nanoparticle-Supported and Magnetically Recoverable Ruthenium Hydroxide Catalyst: Efficient Hydration of Nitriles to Amides in Aqueous Medium, Polshettiwar et. al. Chem. Eur. J. 2009, 15, 1582-1586.
During the past decade, organocatalysis, a metal-free approach to the synthesis of organic molecules, has become a significant area of research. A diverse set of reactions, including enantioselective C—C, C—N, C—O bond formation, Diels-Alder, Baylis-Hilman, Mannich, Michael, Friedel-Crafts alkylation, oxidation, and carbohydrate synthesis, has benefited from the developments in this area. The advent and development of organocatalysis, MacMillan, Nature 2008, 455, 304-308. This relatively green approach has been rendered even greener by efforts in immobilization and recycling of the organocatalysts on supports, which involve their adsorption, covalent linkage, and dissolution in various matrices. Supported proline and proline-derivatives as recyclable organocatalysts, Gruttadauria et al., Chem. Soc. Rev. 2008, 37, 1666-88; Asymmetric Organocatalytic Domino Reactions, Karimi et al., Angew Chem. Int. Ed. 2007, 46, 7210-7213; Asymmetric Aldol Reaction Catalyzed by a Heterogenized Proline on a Mesoporous Support. The Role of the Nature of Solvents, Doyaguez et al., J. Org. Chem. 2007, 72, 9353-56; Magnetic nanoparticle-supported proline as a recyclable and recoverable ligand for the CuI catalyzed arylation of nitrogen nucleophiles, Chouhan et al. Chem. Commun. 2007, 4809-4811. Newer strategies include the use of non-traditional methods such as light, mechanochemical mixing, microwave (MW), and ultrasonic irradiation. Most of these reactions are generally carried out in organic solvents, with a few aqueous phase organocatalytic processes as recent exceptions. Enamine-Based Aldol Organocatalysis in Water: Are They Really “All Wet”?, Brogan et al., Angew. Chem. Int. Ed. 2006, 45, 8100-02; Combined Proline-Surfactant Organocatalyst for the Highly Diastereo- and Enantioselective Aqueous Direct Cross-Aldol Reaction of Aldehydes, Hayashi et al., Angew Chem. Int. Ed. 2006, 45, 5527-29; Asymmetric Diels-Alder Reactions of a,b-Unsaturated Aldehydes Catalyzed by a Diatylprolinol Silyl Ether Salt in the Presence of Water, Hayashi et al., Angew Chem. Int. Ed. 2008, 47, 6634-37; Highly Efficient Asymmetric Direct Stoichiometric Aldol Reactions on/in Water, Huang et al., Angew Chem. Int. Ed. 2007, 46, 9073-77. Although water is an environmental benign solvent, and addition of water often accelerates the reaction, isolation of final organic product from a reaction mixture is often tedious. Most of the reactions described in published reports use excessive amounts of toxic organic solvents for workup and the total amount of water used in the process is much less. Environmental and economic aspects of both the reaction step and the product workup stage are important and are key to determining the greenness of aqueous protocols.
The efficiency of MW flash-heating has resulted in dramatic reductions in reaction times, reduced from days to minutes, which is potentially important in process chemistry for the expedient generation of fine chemicals. Microwave-Assisted Organic Synthesis and Transformations using Benign Reaction Media, Polshettiwar et. al. Acc. Chem. Res. 2008, 5, 629-639. Microwaves initiate rapid intense heating of polar molecules such as water while non-polar molecules do not absorb the radiation and in turn not heated. It was also established that the use of water was advantageous in microwave chemistry and expedited the protocol with more energy efficiency. Selective heating can also be exploited in heterogeneous catalysis protocols. Aqueous microwave chemistry: a clean and green synthetic tool for rapid drug discovery, Polshettiwar et. al. Chem. Soc. Rev. 2008, 37, 1546-1557.
The nano-supported, magnetically recyclable organocatalysts of embodiments of the present invention may be used for various organocatalytic reactions, including but not limited to Paal-Knorr reactions, aza-Michael additions and pyrazole synthesis.
The Paal-Knorr reaction in which amines are converted to pyrrole in one step has gained great interest in the synthetic organic chemistry because these heterocycles are intermediates for various pharmaceutical drugs. A range of clean protocols has been developed by using solid supported catalysts such as alumina, zeolites, phosphates, and ionic liquids. 2,5-Dialkylfurans and Nitroalkanes as Source of 2,3,5-Trialkylpyrroles, Ballini et al., Synlett 2000, 391-93; Layered zirconium phosphate and phosphonate as heterogeneous catalyst in the preparation of pyrroles, Curini et al., Tetrahedron Lett. 2003, 44, 3923-25; Pyrrole synthesis in ionic liquids by Paal-Knorr condensation under mild conditions, Wang et al., Tetrahedron Lett. 2004, 45, 3417-19. The use of non-conventional energy sources such as microwave and ultrasound has also been studied. However, most of the above methods involve the use of excess amounts of catalyst, toxic organic solvents and tedious workup and cannot be considered as real green protocols. Further, the inventors are not aware that this reaction has ever been accomplished using an organocatalyst.
Aza-Michael addition is a vital carbon-nitrogen bond-forming reaction and has been intensively examined as a powerful tool in organic synthesis. However, most of the aza-Michael additions are performed in organic solvents. Recently β-cyclodextrin, ytterbium triflate, surfactant-type asymmetric organocatalyst (STAO) type catalyst and polystyrenesulfonic acid, have been used in aqueous medium. β-Cyclodextrin promoted aza-Michael addition of amines to conjugated alkenes in water, Surendra et al., Tetrahedron Lett. 2006, 47, 2125-27; Expanding the Scope of Lewis Acid Catalysis in Water: Remarkable Ligand Acceleration of Aqueous Ytterbium Triflate Catalyzed Michael Addition Reactions, Ding et al., J. Org. Chem. 2006, 71, 352-55; Surfactant-type asymmetric organocatalyst: organocatalytic asymmetric Michael addition to nitrostyrenes in water, Luo et al., Chem. Commun. 2006, 3687-89; Tandem bis-aza-Michael addition reaction of amines in aqueous medium promoted by polystyrenesulfonic acid, Polshettiwar et al. Tetrahedron Letters 2007, 48, 8735-8738. Although today's environmental concerns encourage the development of such greener synthetic methodology in aqueous medium, many of these methods suffer from limitations such as the use of expensive and toxic catalysts and harsh reaction conditions.
Pyrazoles are an important class of bio-active drug targets in the pharmaceutical industry, in both lead identification and lead optimization processes. Recently, several efficient methods have been developed (Reaction of N-Monosubstituted Hydrazones with Nitroolefins: A Novel Regioselective Pyrazole Synthesis, Deng et al., Org. Lett. 2006, 8, 3505-08 and references cited therein, Greener and rapid access to bio-active heterocycles: room temperature synthesis of pyrazoles and diazepines in aqueous medium, Polshettiwar et al. Tetrahedron Letters 2008, 49, 397-400); however most of these utilize a circuitous route requiring longer reaction times, and are often conducted in organic solvents. Although organocatalysis has been extensively explored, much remains to be accomplished, especially in the context of a truly sustainable protocol.
Thus, there is a need for “green” catalysts and, further, a need for benign aqueous protocols that do not use any organic solvent in the reaction or during the workup.